【文章名】Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H4 Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models.
Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H4 Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models.
作者
Cowart, Marlon D.;Altenbach, Robert J.;Liu, Huaqing;Hsieh, Gin C.;Drizin, Irene;Milicic, Ivan;Miller, Thomas R.;Witte, David G.;Wishart, Neil;Fix-Stenzel, Shannon R.;McPherson, Michael J.;Adair, Ronald M.;Wetter, Jill M.;Bettencourt, Brian M.;Marsh, Kenna
[摘要]：designed based on rotationally restricted 2,4-diaminopyrimidines. Series compds. showed potent and selective in vitro H4 antagonism across multiple species, good CNS penetration, improved PK properties compared to ref. H4 antagonists, functional H4 antagonism in cellular and in vivo pharmacol. assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compd., (I, A-943931), combined the best features of the series in a single mol. and is an excellent tool compd. to probe H4 pharmacol. It is a potent H4 antagonist in functional assays across species (FLIPR Ca2+ flux, Kb < 5.7 nM), has high (>190? selectivity for H4, and combines good PK in rats and mice (t1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED50 = 37 mmol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED50 = 72 mmol/kg, rat).
